The hydroamination (HA) reaction involves the addition of an N—H bond across a double or triple bond, furnishing valuable nitrogen containing molecules from readily available and non-hazardous precursors with 100% atom economy, making it one of the most desirable processes, economically and environmentally. Alkenes containing electron withdrawing substituents are more susceptible to nucleophilic attack by alkyl amines, and these so called aza-Michael addition reactions may occur in the absence of catalysts. However, in many cases the reaction has an unfavourable ΔG0 and gave poor yields even at extremely high reaction temperatures and pressures.
Very few catalysts can facilitate the addition of N—H to double bonds (hydroamination/aza-Michael addition reaction) with high enantioselectivity. Prior to the current invention, only three late transition metal catalysts are known to generate ee values of ≧90%. These are an iridium-fluoride system which promotes the addition of aniline to norbonene (24%, 91% ee), palladium-catalysed addition of primary aromatic amines to 1,3-dienes (up to 95% ee) and nickel-catalysed addition of secondary aromatic amines to alkenoyl-N-oxazolidinones (up to 90% ee). In the examples using palladium or nickel catalysed reactions, catalyst loadings of 5 mol % were employed at room temperature, but reaction times of between 40 h to 5 days were required to achieve significant yields.
The enantioselective addition of primary and secondary aromatic amines to alkenoyl-N-oxazolidinones, catalysed by the cationic palladium complex [(R-BINAP)Pd(solvate)2]2+[TfO]−2, with ee's up to 93%, has recently been reported. It is postulated that the observed addition occurs via a catalytic intermediate as illustrated below
wherein activation of the unsaturated double bond occurs due to the chelation of oxazolidinone functionality to the metal centre. Formation of the catalytic intermediate is favoured due to the sterically hindered conformation of the alkenoyl-N-oxazolidinone. Both ketone functionalities are held in the correct orientation to interact with the palladium metal, thereby facilitating the formation of the catalytic intermediate and ultimately the enantiomerically selective addition of the aromatic amine to the alkenoyl-N-oxazolidinone.
While the use of the alkenoyl-N-oxazolidinones provides a useful route to such important compounds as beta amino acids and derivatives thereof, the use of such sterically hindered oxazolidinones is not always desirable or practicable. There is therefore a need in the art for a process for the hydroamination of less sterically hindered alkenes.